Irritability is an important yet understudied symptom domain in adult patients with major depressive disorder (MDD). Across multiple clinical trials and psychiatric illnesses, we have found that irritability is associated with suicidality and changes in irritability predicts subsequent suicidality, both independent of depressive symptoms.

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BackgroundChildren with neurodevelopmental disorders are at increased risk of developing depression. Irritability predicts depression in the general population and is common in children with neurodevelopmental disorders. Thus, it is possible that irritability in children with neurodevelopmental disorders contributes to the link with later depression. This study aimed to (a) examine the association between childhood neurodevelopmental difficulties and adolescent depression and (b) test whether irritability explains this association.MethodsChildren with any neurodevelopmental difficulty at the age of 7–9 (n = 1,697) and a selected, comparison group without any neurodevelopmental difficulty (n = 3,177) were identified from a prospective, UK population‐based cohort, the Avon Longitudinal Study of Parents and Children. Neurodevelopmental difficulties were defined as a score in the bottom 5% of the sample on at least one measure of cognitive ability, communication, autism spectrum symptoms, attention‐deficit/hyperactivity symptoms, reading or motor coordination. The Development and Well‐Being Assessment measured parent‐reported child irritability at the age of 7, parent‐reported adolescent depression at the age of 10 and 13, and self‐reported depression at the age of 15. Depression measures were combined, deriving an outcome of major depressive disorder (MDD) in adolescence. Logistic regression examined the association between childhood neurodevelopmental difficulties and adolescent MDD, controlling for gender. Path analysis estimated the proportion of this association explained by irritability. Analyses were repeated for individual neurodevelopmental problems.ResultsChildhood neurodevelopmental difficulties were associated with adolescent MDD (OR = 2.11, 95% CI = 1.24, 3.60, p = .006). Childhood irritability statistically accounted for 42% of this association. On examining each neurodevelopmental difficulty separately, autistic, communication and ADHD problems were each associated with depression, with irritability explaining 29%–51% of these links.ConclusionsChildhood irritability appears to be a key contributor to the link between childhood neurodevelopmental difficulties and adolescent MDD. High rates of irritability in children with autistic and ADHD difficulties may explain elevated rates of depression in the neurodevelopmental group.

Irritability is a common feature of many psychiatric disorders, including both externalizing and internalizing disorders. There is little research, however, examining associations between irritability and these symptom domains, particularly during the important developmental period of adolescence, characterized by sex differences in the prevalence of disorders. We examined the cross-sectional associations between irritability, measured with the Affective Reactivity Index, and symptoms of externalizing and internalizing domains of psychopathology, measured with the Youth Self Report, in a volunteer community sample (N = 183) of 9- to 13-year-old (M = 11.39, SD = 1.07) boys and girls (37% White/Caucasian, 8% Asian, 11% Hispanic, 8% African American, 2% Native American, 2% Pacific Islander, 28% Other, and 3% not reported). A subset of the sample (n = 112) provided data at a 2-year follow-up, used to extend these associations. There were no sex differences in levels of irritability; however, the associations between irritability and symptom domains were moderated by sex. Specifically, in girls, irritability was associated equally with externalizing and internalizing symptoms. In contrast, in boys, irritability was associated more strongly with externalizing symptoms than with internalizing symptoms. Thus, across both sexes, irritability was moderately associated with externalizing symptoms, but the association between irritability and internalizing symptoms was stronger in girls than in boys. At follow-up, sex moderated the association between baseline irritability and later externalizing and internalizing symptoms. These findings indicate that irritability is associated with both externalizing and internalizing symptoms in early adolescence and that irritability is associated with internalizing symptoms more strongly in girls than in boys.

There is evidence to suggest that a modular approach to the treatment of adolescent depression outperforms evidence-based treatments that exclusively target a single problem domain (eg, anxiety or depression). This has yet to be tested in an inpatient setting or through a group-based approach to care. This preliminary study conducted at the NIH evaluates the effectiveness of the evidence-based treatment, such as the Modular Approach to Therapy for Children with Anxiety, Depression, Trauma or Conduct Problems (MATCH-ADTC), as delivered via individual and group-based sessions to depressed adolescents with comorbid anxiety during their inpatient admissions to the adolescent behavioral health unit (1SW).

IMPORTANCE Comorbidity is ubiquitous in psychiatry, but it is unclear how to differentiate neural mechanisms of co-occurring symptoms. Pediatric irritability and anxiety symptoms are prevalent and frequently co-occur. Threat orienting is pertinent to both phenotypes and is an ideal context in which to examine their unique and common neural mechanisms. OBJECTIVES To decompose the unique and shared variances of pediatric irritability and anxiety symptoms and to determine neural correlates of these differentiated phenotypes during threat orienting. DESIGN, SETTING, AND PARTICIPANTS This investigationwas a cross-sectional functional magnetic resonance imaging study. The setting was a research clinic at the National Institute of Mental Health. Participants were youth aged 8 to 18 years spanning multiple diagnostic categories (141 youth with disruptive mood dysregulation disorder, anxiety disorder, and/or attention-deficit/hyperactivity disorder and 56 healthy youth). This combination provided wide variation in levels of irritability and anxiety symptoms. Data were acquired between June 30, 2012, and June 28, 2016. MAIN OUTCOMES AND MEASURES Participants and parents rated youth's irritability on the Affective Reactivity Index and anxiety on the Screen for Child Anxiety Related Emotional Disorders. Bifactor analysis decomposed the unique and shared variances. A functional magnetic resonance imaging dot-probe task assessed attention orienting to angry (ie, threat) vs neutral faces. Whole-brain analyses examined associations between the bifactor-derived phenotypes and both neural activity and amygdala functional connectivity. RESULTS Among 197 participants included in the final analysis, the mean (SD) age was 13.1 (2.7) years, and 91 (46.2%) were female. The best-fit bifactor model (Comparative Fit Index, 0.959; Root Mean Square Error of Approximation, 0.066) included unique factors of parent-reported irritability, youth-reported irritability, and anxiety, as well as a common factor of negative affectivity. When the task required attention away from threat, higher parent-reported irritability was associated with increased activity in the insula, caudate, dorsolateral and ventrolateral prefrontal cortex, and inferior parietal lobule (t(189) >= 4.15 for all, P<.001 for all). In contrast, higher anxiety was associated with decreased amygdala connectivity to the cingulate, thalamus, and precentral gyrus (t(189) <= -4.19 for all, P<.001 for all). These distinctive neural correlates did not emerge using a diagnostic approach. CONCLUSIONS AND RELEVANCE A latent variable approach to parsing co-occurring symptom dimensions revealed a novel double dissociation. During orientation away from threat, only irritability was associated with neural activity, whereas only anxiety was associated with amygdala connectivity. Despite the challenges of symptom co-occurrence for clinical neuroscience, data-driven phenotypingmay facilitate a path forward.

In 671 mother–child (49% male) pairs from an epidemiological birth cohort, we investigated (a) prospective associations between DNA methylation (at birth) and trajectories (ages 7–13) of oppositional defiant disorder (ODD), and the ODD subdimensions of irritable and headstrong; (b) common biological pathways, indexed by DNA methylation, between ODD trajectories and attention deficit hyperactivity disorder (ADHD); (c) genetic influence on DNA methylation; and (d) prenatal risk exposure associations. Methylome‐wide significant associations were identified for the ODD and headstrong, but not for irritable. Overlap analysis indicated biological correlates between ODD, headstrong, and ADHD. DNA methylation in ODD and headstrong was (to a degree) genetically influenced. DNA methylation associated with prenatal risk exposures of maternal anxiety (headstrong) and cigarette smoking (ODD and headstrong).

BACKGROUND:Irritability is one of the most common reasons for referral to child and adolescent mental health services and is the main characteristic of the new diagnosis of disruptive mood dysregulation disorder (DMDD). However, the recognition and management of irritability presents a major challenge in clinical practice and may be partly responsible for the dramatic increase in antipsychotic prescribing in recent years.METHODS:In this review, we provide up-to-date information on the definition and mechanisms underlying irritability, and its assessment in clinical practice. We aim to discuss the latest research on DMDD, and the presence of severe irritability in the context of other disorders, as well as to recommend a treatment algorithm.RESULTS:Severe irritability is associated with aberrant reward processing and bias toward threatening stimuli. Several measures are available to easily assess irritability. The recent diagnosis of DMDD captures children whose main problem is severe irritability and differ from those with bipolar disorder in longitudinal outcomes, family history, and behavioral and neural correlates. Treatment of irritability might depend on the context it appears. Indirect evidence suggests that parent management training (PMT) and cognitive behavioral therapy (CBT) are the most supported psychological treatments for irritability.CONCLUSIONS:Irritability, recognized as a mood problem rather than a purely behavioral manifestation, is a common condition for young people. Practitioners should not ignore irritability as it is associated with substantial morbidity and impairment. Although there are no trials with irritability as main outcome, clinicians can apply several existing pharmacological and psychological interventions for its treatment. Also, new promising approaches relying on pathophysiological findings, such as exposure-based cognitive behavioral therapy techniques and interpretation bias training (IBT), are being currently investigated.

BackgroundIrritability, a frequent complaint in children with psychiatric disorders, reflects increased predisposition to anger. Preliminary work in pediatric clinical samples links irritability to attention bias to threat, and the current study examines this association in a large population-based sample.MethodsWe studied 1,872 children (ages 6-14) using the Development and Well-Being Assessment (DAWBA), Childhood Behavior Checklist (CBCL), and dot-probe tasks. Irritability was defined using CBCL items that assessed temper tantrums and hot temper. The dot-probe task assessed attention biases for threat-related (angry face) stimuli. Multiple regression analysis was used to assess specificity of associations to irritability when adjusting for demographic variables and co-occurring psychiatric traits. Propensity score matching analysis was used to increase causal inference when matching for demographic variables and co-occurring psychiatric traits.ResultsIrritability was associated with increased attention bias toward threat-related cues. Multiple regression analysis suggests associations between irritability and threat bias are independent from demographic variables, anxiety, and externalizing traits (attention-deficit/hyperactivity, conduct, and headstrong/hurtful), but not from broad internalizing symptoms. Propensity score matching analysis indicated that this association was found for irritable versus nonirritable groups matched on demographic and co-occurring traits including internalizing symptoms.ConclusionsIrritability in children is associated with biased attention toward threatening information. This finding, if replicated, warrants further investigation to examine the extent to which it contributes to chronic irritability and to explore possible treatment implications.

Maternal depression in the peri‐natal period is associated with increased risk for young adult depression in offspring. This study explored mediation of these links via trajectories of child conduct and emotional problems (Strengths and Difficulties Questionnaire) from ages 4–16 years old in data from the Avon Longitudinal Study of Parents and Children cohort (n = 13373). Through gender‐specific structural equation models, a composite measure of exposure to early maternal depression (Edinburgh Postnatal Depression Scale), predicted young adult depression at age 18 (Revised Clinical Interview Schedule – distal outcome). Mediational effects were then estimated by testing which parts of joint piecewise latent trajectory models for child/adolescent conduct and emotional problems were associated with both exposure and distal outcome. For girls, only conduct problems in early childhood were consistently indicated to mediate effects of early maternal depression on risk of young adulthood depression. Some evidence for a pathway via changing levels of childhood and adolescent emotional difficulties was also suggested. For boys, by contrast, the differing models gave less consistent findings providing some evidence for a small time‐specific indirect effect via early childhood conduct problems. In addition to its practice implications the current methodological application offers considerable potential in exploratory longitudinal developmental mediation studies. © 2016 The Authors International Journal of Methods in Psychiatric Research Published by John Wiley & Sons Ltd

Objective: Clinically impairing irritability affects 25% to 45% of children with attention-deficit/hyperactivity disorder (ADHD); yet, we know little about what interventions are effective in treating children with ADHD and co-occurring irritability. We used data from the Multimodal Treatment Study of Children With ADHD (MTA) to address 3 aims: to establish whether irritability in children with ADHD can be distinguished from other symptoms of oppositional defiant disorder (ODD); to examine whether ADHD treatment is effective in treating irritability; and to examine how irritability influences ADHD treatment outcomes.Method: Secondary analyses of data from the MTA included multivariate analyses, and intent-to-treat randomeffects regression models were used.Results: Irritability was separable from other ODD symptoms. For treating irritability, systematic stimulant treatment was superior to behavioral management but not to routine community care; a combination of stimulants and behavioral treatment was superior to community care and to behavioral treatment alone, but not to medication alone. Irritability did not moderate the impact of treatment on parent- and teacher-reported ADHD symptoms in any of the 4 treatment groups.Conclusion: Treatments targeting ADHD symptoms are helpful for improving irritability in children with ADHD. Moreover, irritability does not appear to influence the response to treatment of ADHD. Clinical trial registration information Multimodal Treatment Study of Children With Attention Deficit and Hyperactivity Disorder (MTA); http://www.clinicaltrials.gov; NCT00000388.

Background: Irritability in people with autism spectrum disorders (ASD) is common and impairing, yet its mechanisms remain understudied. We investigated symptom reporting and mechanisms of irritability in ASD, focusing on the relation between irritability and physiological stress responses. Methods: Forty-seven unmedicated boys with high-functioning ASD (hfASD) and 23 typically developing boys aged 10-16 years completed a psychosocial stress test. Changes in cortisol, heart rate and heart rate variability throughout the test were recorded. Self-and parent-reported measures of irritability were obtained. Irritability symptom reporting in the hfASD group was compared to two groups of boys without ASD: highly irritable boys (severe mood dysregulation, SMD; n = 40) and healthy-control boys (HC; n = 30). Results: Boys with hfASD scored significantly higher on irritability than HC boys, and they reported a pattern of irritability symptoms closely resembling that of boys with SMD. The internal consistency of irritability in hfASD was high by parent-and self-report. Although boys with hfASD showed significant stress-induced changes in cortisol and heart rate, those who rated themselves as highly irritable had lower cortisol levels throughout the test compared to those low on irritability. Participants rated as highly irritable by their parents showed blunted cortisol and heart rate responses to stress. The effects of irritability on heart rate, but not cortisol, were accounted for by trait anxiety. Conclusions: Irritability can be measured reliably in hfASD and is associated with distinct biological responses to stress.

Rates of illness can vary by geographic location. One only has to wander the streets of a western capital after visiting parts of the developing world to see why obesity threatens affluent societies. Rates of disease also vary by time. Gastric carcinoma, once the most common cause of cancer death in the United States and Europe, now lags well behind other malignancies. Environmental factors—including lifestyle choices—drive variation in obesity and gastric tumors, as with alcohol consumption, smoking, and common forms of heart disease.

BackgroundIt has been reported that mania may be associated with superior cognitive performance. In this study, we test the hypothesis that manic symptoms in youth separate along two correlated dimensions and that a symptom constellation of high energy and cheerfulness is associated with superior cognitive performance.MethodWe studied 1755 participants of the IMAGEN study, of average age 14.4years (SD=0.43), 50.7% girls. Manic symptoms were assessed using the Development and Wellbeing Assessment by interviewing parents and young people. Cognition was assessed using the Wechsler Intelligence Scale For Children (WISC-IV) and a response inhibition task.ResultsManic symptoms in youth formed two correlated dimensions: one termed exuberance, characterized by high energy and cheerfulness and one of undercontrol with distractibility, irritability and risk-taking behavior. Only the undercontrol, but not the exuberant dimension, was independently associated with measures of psychosocial impairment. In multivariate regression models, the exuberant, but not the undercontrolled, dimension was positively and significantly associated with verbal IQ by both parent- and self-report; conversely, the undercontrolled, but not the exuberant, dimension was associated with poor performance in a response inhibition task.ConclusionsOur findings suggest that manic symptoms in youth may form dimensions with distinct correlates. The results are in keeping with previous findings about superior performance associated with mania. Further research is required to study etiological differences between these symptom dimensions and their implications for clinical practice.

BACKGROUND:Severe, chronic irritability is receiving increased research attention, and is the cardinal symptom of a new diagnostic category, disruptive mood dysregulation disorder (DMDD). Although data from epidemiological community samples suggest that childhood chronic irritability predicts unipolar depression and anxiety in adulthood, whether these symptoms are stable and cause ongoing clinical impairment is unknown. The present study presents 4-year prospective and longitudinal diagnostic and impairment data on a clinical sample of children selected for symptoms of severe irritability (operationalized as severe mood dysregulation [SMD]). METHODS:Youth meeting criteria for SMD (n = 200) were evaluated at baseline using standard diagnostic methods. Two-year (n = 78) and 4-year (n = 46) follow-up diagnostic and clinical impairment ratings collected at 6-month intervals were completed with those youths enrolled in the study for a sufficient time. RESULTS:Although the number of youth meeting strict categorical SMD criteria declined over time (49 and 40% at 2 and 4 years, respectively), many individuals not meeting full criteria continued to display clinically significant irritability symptoms (2 years: 42%; 4 years: 37%). Impairment due to these irritability symptoms remained consistently in the moderate range on the Clinical Global Impressions Scale. CONCLUSIONS:By the 4-year follow-up, only 40% of youths meet strict SMD criteria; however, most continue to display clinically impairing symptoms and significant impairment warranting psychiatric treatment. These findings provide evidence for the course of irritability, with implications for DMDD. Future research with populations meeting DMDD criteria and followed through the ages of high risk for psychiatric diagnoses is necessary.

BACKGROUND:Temper outbursts in youth with obsessive-compulsive disorder (OCD) are a common source of concern, but remain poorly understood. This study examined a set of hypotheses related to: (a) the prevalence of temper outbursts in paediatric OCD, (b) the associations of temper outbursts with OCD severity and depressive symptoms; and (c) the influence of temper outbursts on treatment response. METHODS:The prevalence of temper outbursts was estimated in a specialist OCD clinical sample (n = 387) using parent- and child-report. This was replicated in a community sample (n = 18,415). Associations of temper outbursts with obsessive-compulsive symptoms and with depressed mood were examined using logistic regression models. The influence of temper outbursts on treatment response was examined in a subsample of 109 patients treated with cognitive behaviour therapy (CBT) with or without medication. RESULTS:Over a third of young people with OCD displayed temper outbursts, and rates were similar across the clinical and community samples. Temper outbursts were two to three times more common in youth with OCD than in healthy controls. However, OCD symptom severity was not a strong predictor of child- or parent-reported temper outbursts. Instead, both child- and parent- reported temper outbursts were significantly associated to depressive symptoms. CBT strongly reduced OCD and depressive symptoms, as well as the severity of temper outbursts. There was no significant difference in post-treatment OCD or depression scores between those with temper outbursts compared to those without. CONCLUSIONS:Temper outbursts are common in youth with OCD and are particularly related to depressed mood. They improve with CBT for OCD and do not seem to impede OCD treatment response.

Our objective was to compare self‐ and parent‐reported irritability in youths with anxiety disorders, healthy youths, and those with mood disorders characterized by irritability. Irritability is a common but relatively understudied psychiatric symptom in child and adolescent anxiety disorders. In anxious youths, little is known about the severity of irritability, its impact on functioning, or the effect of informant source on reports of irritability.